FR2578543A1 - Antihypertension spiroamidoamino compounds - Google Patents

Abstract

Compounds corresponding to the general formula: and their pharmaceutically acceptable salts. These compounds have an antihypertension activity.

Description

SPIRO-AMIDOAMINO ANTI-HYPERTENSIVE COMPOUNDS
The present patent application relates to compounds, their pharmaceutically acceptable salts, and pharmaceutical preparations made therefrom, useful in the treatment of hypertension in subjects suffering from hypertension.

et leurs sels d'addition aux acides, leurs sels de métaux alcalins et leurs sels de métaux alcalinoterreux pharmaceutiquement acceptables, dans laquelle
Q est Y1-C(O) -C*H(R1)-NH-, -NH2, R1C (O) -S-C H(Rl))O-l-, ou HS-(C*H (R1))@-1-
Y1 et Y2 sont indépendamment - OH, -OR ou -NR1R2
Z est

ou N
x ou y est égal à 1 et l'autre est égal à 0
R est indépendamment l'hydrogène, un alkyle en
C1- C8 , un aryle ayant jusqu'à 12 atomes de carbone, un aryle-alkyle dans lequel la partie aryle a jusqu'à 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle ayant 3 à 10 atomes de carbone, un cycloalkylaryle condensé ayant 8 à 12 atomes de carbone, un hétérocyclique ou un alkyle amino-substitué ayant 1 à 6 atomes de carbone ;
R1 est indépendamment l'hydrogène, un alkyle ayant 1 à 8 atomes de carbone, un aryle ayant jusqu'à 12 atomes de carbone, un aryl -alkyle dans lequel la partie aryle a jusqu'à 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle ayant 3 à 10 atomes de carbone, un cycloalkylaryle condensé ayant 8 à 12 atomes de carbone, un hétérocyclique, ou un groupe alkyle amino-substitué ayant 1 à 6 atomes de carbone ;;
R2 est indépendamment l'hydrogène, un alkyle ayant 1 à 8 atomes de carbone, un aryle ayant jusqu'à 12 atomes de carbone, un aryl -alkyle dans lequel la partie aryle à jusqu'à 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle ayant 3 à 10 atomes de carbone, un cycloalkylaryle condensé ayant 8 à 12 atomes de carbone, un hétérocyclique ou un groupe alkyle amino-substitué ayant 1 à 6 atomes-de carbone ;;
R3 est un -OR, phényl, ou un groupe alkyle ou alcoxy ayant jusqu'à 6 atomes de carbone
R4 et R5 sont indépendamment l'hydrogène, un alkyle ayant 1 à 8 atomes de carbone, un aryle ayant jusqu'à 12 atomes de carbone, un alkyl -aryle dans lequel la partie aryle a jusqu'd 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle ayant 3 à 1-0 atomes de carbone, un cycloalkylaryle condensé ayant 8 à- 12 atomes de carbone, un hétérocyclique, ou un groupe alkyle amino-substitué ayant 1 à 6 atomes de carbone
R6 est indépendamment l'hydrogène, un alkyle ayant 1 à 8 atomes de carbone, un aryle ayant jusqu'à 12 atomes de carbone, un aryl -alkyle dans lequel la partie aryle a jusqu'a 10 atomes de carbone et la partie alkyle a 1 à 6 atomes de carbone, un cycloalkyle ayant 3 à 10 atomes de carbone, un cycloalkylaryle condensé ayant 8 à 12 atomes de carbone, un groupe hétérocyclique ou un groupe alkyle amino-substitué ayant 1 à 6 atomes de carbone
A,-B et E sont indépendamment l'hydrogène, un halogène, -OH, -OR, -CF3, -NR1R2, -C (O) Y1, -SO2R, ou -SO2NR1R2, pourvu qu'au moins deux des radicaux A, B et E ne soient pas l'hydrogène
X1 est-(ch2)1-, - (CH2)bS(ch2)c-,
(CH2)b N(R) (CH2)C-, -(CH2)b C(O) (CH2)c-, (CH2)bCH(R3) (GH2)çi

In general, the present invention comprises compounds corresponding to formula (1)

and their acid addition salts, their alkali metal salts and their pharmaceutically acceptable alkaline earth metal salts, wherein
Q is Y1-C (O) -C * H (R1) -NH-, -NH2, R1C (O) -SC H (Rl)) Ol-, or HS- (C * H (R1)) @ - 1 -
Y1 and Y2 are independently - OH, -OR or -NR1R2
Z is

or N
x or y is 1 and the other is 0
R is independently hydrogen, alkyl
C1- C8, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic or amino-substituted alkyl having 1 to 6 carbon atoms;
R1 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic, or an amino-substituted alkyl group having 1 to 6 carbon atoms;
R2 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an arylalkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic or an amino-substituted alkyl group having 1 to 6 carbon atoms;
R3 is -OR, phenyl, or an alkyl or alkoxy group having up to 6 carbon atoms
R4 and R5 are independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an alkylaryl in which the aryl part has up to 10 carbon atoms and the part alkyl has 1 to 6 carbon atoms, a cycloalkyl having 3 to 1-0 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic, or an amino-substituted alkyl group having 1 to 6 carbon atoms
R6 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or an amino-substituted alkyl group having 1 to 6 carbon atoms
A, -B and E are independently hydrogen, halogen, -OH, -OR, -CF3, -NR1R2, -C (O) Y1, -SO2R, or -SO2NR1R2, provided that at least two of the radicals A , B and E are not hydrogen
X1 is- (ch2) 1-, - (CH2) bS (ch2) c-,
(CH2) b N (R) (CH2) C-, - (CH2) b C (O) (CH2) c-, (CH2) bCH (R3) (GH2) çi

X2 is- (CH2) d-, - (CH2) eS (CH2) f-,
(CH2) bN (R) (CH2) c-, - (CH2) e C (O) (CH2) f-, or
(CH2) e CH (R3) (CH2) f-;
provided that a, b, c, d, e, f, g and h are each zero or a positive integer up to 6, and are chosen so that the ring formed by X1, X2 and the two atoms to which they are fixed, contain 5 to 8 atoms; or the condensed alkyl, cycloalkyl, aryl and aryl-cycloalkyl groups can carry substituents chosen from the group consisting of an alkyl having 1 to 6 carbon atoms, an alkoxy having 1 to 6 carbon atoms, -CF3, - OH, -SH, halogen, -NO2, and -COOR.

et R2 est de préférence NH2(CH2)4
R6 est H ; un alkyle ayant 1 à 8 atomes de carbone ; un alkyle amino-substitué ayant 1 à 6 atomes de carbone ; ou un phényle ou un phényl-alkyle en C1-6 ;
A est -NH2 , -OH , un phénoxy ; un alcoxy ayant jusqu'à 6 atomes de carbone ; -SO2NR1R2 où R1 et R2 sont l'hydrogène ou un alkyle en C1 à C31 ou de préfé- rence tous les deux l'hydrogène ;
B est un halogène, et de préférence un chloro, ou -CF3
et E est un halogène ou l'hydrogène.Preferred substituents within the scope of the present invention include those in which
Y1 and Y2 are independently hydroxy, benzyloxy or alkoxy containing up to 8 carbon atoms
Rlest H; alkyl having 1 to 8 carbon atoms; phenylalkyl in which the alkyl has 1 to 4 carbon atoms, and preferably phenethyl; or an indanylf, for example a 2-indanyl;
R2 is H; an alkyl having i to 8 carbon atoms; or an alkyl group having 1 to 8 carbon atoms, which is substituted by an amino or an amino derivative such as -NH2 '-NH-C (NH2) = NH2 or

and R2 is preferably NH2 (CH2) 4
R6 is H; an alkyl having 1 to 8 carbon atoms; amino-substituted alkyl having 1 to 6 carbon atoms; or phenyl or phenyl C1-6 alkyl;
A is -NH2, -OH, phenoxy; an alkoxy having up to 6 carbon atoms; -SO2NR1R2 where R1 and R2 are hydrogen or C1 to C31 alkyl or preferably both hydrogen;
B is a halogen, and preferably a chloro, or -CF3
and E is halogen or hydrogen.

 The ring formed by X1, X2, and the atoms to which they are linked contains a total of 5 to 8 atoms.

et
X1 et X2 sont tous deux -(CH2)2-. X1 et X2 peuvent être substitués avec un groupe R3 qui est de préférence un -OH ou un alkyle contenant de 1 à 6 atomes de carbone.In a preferred embodiment, Z is

and
X1 and X2 are both - (CH2) 2-. X1 and X2 can be substituted with a group R3 which is preferably an -OH or an alkyl containing from 1 to 6 carbon atoms.

Preferred substituents for R4 and R5 are -H, or alkyl having 1 to 2 carbon atoms.

 Alkyl groups include straight and branched chain groups, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, amyl, iso-amyl, hexyl, etc. By halogen is meant a chloro, a bromo, an iodo and a fluoro.

 Preferred substituents for R1, R2 and / or R6 also include cycloalkyl groups, aryl groups, heterocyclic groups, and fused aryl-cycloalkyl groups, as defined herein, any of which can be linked to the main chain of the molecule (1) directly or via an alkylene bridge - (CH2) n - where n is a number from 1 to 6. The preferred cycloalkyl groups include the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl groups, or norbornyle.

Preferred condensed aryl and aryl-cycloalkyl groups include phenyl, indolyl, indolino, indanyl, naphthyl, tetrahydronaphthyl, and decahydronaphthyl. Preferred heterocyclic groups include pyridyl, thienyl, furyl, furfuryl, tetrahydrofuryl, quinoleyl, isoquinoleyl, tetrahydroquinoleyl, tetrahydroisoquinoleyl, decahydroquinoleyl, decahydroisoquinoleyl, pyrrolyl, pyrololidyl, pyrololidyl. Preferred aryl-alkyl substituents include benzyl and phenethyl. Preferred substituents on condensed alkyl, cycloalkyl, aryl and aryl-cycloalkyl substituents include C1-C6 alkyl and alkoxy, -CF3, -OH, -NH2, phenoxy, -NR1R2, -COOH, -CN, -SH, a halogen, -NO2, and COOR, and preferably a COO-C1 -C6 alkyl.

The compounds according to formula (1) may contain asymmetric centers on the marked carbon atoms: C *. Each of these carbon atoms can have an (R) or (S) configuration, preferably (S). In the preferred compounds, the spiro carbon is (S) or (R) and the other asymmetric carbons are in the (S) configuration. Individual optical diastereoisomers and mixtures thereof are considered to fall within the scope of the invention
When diastereoisomeric products result from the synthesis procedures, the desired diastereoisomeric product can be separated by conventional chromatographic or fractional crystallization methods.

avec un composé répondant à la formule (3)

The compounds corresponding to formula (1) can be prepared by coupling of a compound corresponding to formula (2)

with a compound corresponding to formula (3)

avec le composé(5)

Compound (3) can be prepared by reacting compound (4)

with compound (5)

The various substituents on the compounds (2), (3), (4) and (5) have the meanings given above.

 Specialists will realize that the coupling of compounds (2) and (3) can be carried out by conventional peptide bonding techniques, for example in the presence of a coupling agent such as DCC (N, N 'dicyclohexylcarbodilmide) or CDI (N, N'-carbonyl diimidazole). It may also be preferable to transform the -COOH group of the compound (2) into -CtO) C1, then react the intermediate obtained with the compound (3).

This is the preferred route when Q contains a sulfur atom. It is also possible, preferably, to transform the compound (2) into the corresponding N-carboxyanhydride (NCA) by letting (2) react with phosgene, then react the N-carboxyanhydride obtained with the compound (3) to give the desired intermediary. The spiro amino intermediate ester can also be prepared by first reacting the compound (2) with the compound (5) in any of the above ways (NCA; acid chloride; or active ester coupling- peptide) to give the intermediate which is then reacted with the compound (4). It will also be seen that the atony of nitrogen which is between the carbon atoms to which R1 and R2 are attached must be protected with a blocking agent such as 2,2,2-trichlorethoxycarbonyl, or benzyloxycarbonyl.

The protective group is then removed, preferably after the compounds (2) and (3) have been linked together.

Other amino substituents, such as NH2 (CH2) 4-, must be protected, then deprotected, in an analogous manner. Likewise, Y1 and Y2 are preferably converted into ethoxy, t-butoxy or benzyloxy, before the intermediates are reacted. If the free acid is desired, it is obtained subsequently by elimination of the esterifying group in a known manner.

 The compounds of the present invention in which one of Y1 and Y2 is -OH and the other is alkyl, such as methoxy or ethoxy, are preferably prepared by reacting the compounds (2) and (3) as indicated above, wherein one of Y1 and Y2 is the desired alkyl ester, and the other is an easily cleaved ester group such as t-butoxy. The amide thus prepared gives the monoesters-monoacids desired by careful acid hydrolysis.

 The compounds of the present invention form salts with various mineral and organic acids and bases which also belong to the field of the invention.

These salts include ammonium salts, alkali metal salts such as sodium and potassium salts (which are preferred), alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases, for example dicyclohexylamine salts, N-methyl-D glucamine, salts with amino acids such as arginine, lysine and the like. It is likewise possible to prepare salts with mineral and organic acids, for example HC1, HBr, H2SO4, H3PO4, as well as methanesulfonic acid, toluenesulfonic acid, maleic acid, acetic acid, malic acid. , citric acid, fumaric acid and camphrosulfonic acid.

Physiologically acceptable non-toxic salts are preferred, although other salts are also useful, for example to isolate or purify the product.

 The salts can be formed by conventional means, for example by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is then removed under vacuum or by freeze-drying, or by exchanging the cations of an existing salt for another cation on an appropriate ion-exchange resin.

 The action of the enzyme renin on angiotensinogen, a pseudoglobulin from human plasma, produces the decapepidide angiotensin Iq Angiotensin I is transformed by the enzyme transforming angiotensin (ACE) into the octal peptide angiotensin II, The latter is an active vasopressor agent which has been implicated as a causative agent in various forms of hypertension in various mammals, for example rats and dogs. The compounds falling within the scope of the invention which intervene in the renin-angiotensin I-angiotensin II sequence inhibit the enzyme transforming angiotensin I, and therefore are useful for reducing or relieving hypertension.

 Furthermore, the compounds within the scope of the present invention which possess diuretic activity promote the relief of hypertension by promoting diuresis and therefore are useful for the treatment of congestive heart failure. The compounds falling within the scope of the invention may also simultaneously possess a 12ACE inhibitory activity and a diuretic activity, which is particularly unexpected in view of the fact that this simultaneous activity cannot be predicted from the compounds of the prior art . Thus, by administration of a composition containing one of the compounds corresponding to formula (1) or a combination of these or their pharmaceutically acceptable salts, hypertension is relieved in the species of mammals which suffer therefrom. A single dose, or preferably two to four divided daily doses, provided on the basis of approximately 0.1 100 mg / kg per day, preferably approximately 1 to 50 mg / kg per day, is suitable for reducing the blood pressure. The substance is preferably administered orally, but a parenteral route such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes can also be used.

 The compounds of the invention can be used to achieve the reduction of blood pressure by formulating one or more of them in compositions such as tablets, capsules or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration. About 10 to 500 mg of a compound or mixture of compounds corresponding to formula (1) or their physiologically acceptable salts are mixed with a physiologically acceptable vehicle, support, excipient, binder, preservative, stabilizer, perfume. dose unit as claimed by established pharmaceutical practice. The amount of active substance in these compositions or preparations is such that an appropriate dose is obtained within the indicated range.

 As examples of the adjuvants which can be incorporated into tablets, capsules, etc., there may be mentioned: a binder such as tragacanth, gum arabic, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, etc. ; ; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a fragrance such as peppermint, sassafras essence or cherry essence.

When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dose unit.

For example, the tablets can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a color and a perfume such as a cherry or orange perfume.

 The sterile compositions for injection may be formulated in accordance with conventional pharmaceutical practice, by dissolving or suspending the active substance in a vehicle such as water for injection, a natural vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or in a synthetic fatty vehicle such as ethyl oleate, etc. Tampons, preservatives, antioxidants, etc. can be incorporated if necessary.

Example 1
A. N- (4- (2,2-dimethyltrimethylene ketal cyclohexylj- ethyl glycinate
A 1,4-cyclohexanedione mono-2,2-dimethyltrimethylene ketal (5.0 g, 0.0240 mole) and the glycine ethyl ester hydrochloride (4.52 g, 0.00360 mole) dissolved in absolute ethanol (125 ml), sodium cyanoborhydride (1.0 g) is added in successive portions, over a period of 45 minutes, with external cooling (ice-water bath). The mixture obtained is stirred overnight at room temperature. The ethanol is evaporated and water is added to the residue, then the reaction mixture is basified to pH 8 with concentrated ammonium hydroxide. The product is extracted three times with chloroform, washed with water, dry over magnesium sulfate, filter and evaporate. The residue is chromatographed on silica gel using chloroform as diluent, which provides the desired product in the form of a light yellow oil.

Composition: calculated for C15H27NO4: C, 62.14
H, 9.56; N, 4.83.

 Found: C, 62.12; H, 9.16; N, 4.23.

B. The hydrochloride of the ethyl ester of N- [4-Spirot6-chloro-3,4 dihydro-7-sulamoyl-1,2R4- benzothiadiazine-1,1-dioxide) cyclohex-1-yl] glycine
N- [4- (2,2-dimethyltrimethylene ketal) ethyl cyclohexylglycinate (6.7 g, 0.0235 mol) and 1-amino-3-chloro-4,6-benzene disulfamide (2, 32 g, 8.15 mmol) in Itethanol (250 ml) which has been previously saturated with anhydrous hydrochloric acid.

The mixture obtained is heated under reflux for three hours. The reaction mixture is cooled to room temperature which provides a solid. Ether is added to the residue, then it is filtered, which gives the desired product in the form of a white solid,
F = 1850C (dtc.).

Composition: calculated for C16H23C1N4O6S2.HCl.2 1 / 2H2O: C, 35.04; H, 5.33;
N, 10.22.

 Found: C, 34.55; H, 5.49; N, 9.61.

C. N-hydrochloride [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl] glycine:
N-r4-spiro ethyl ester hydrochloride (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-ylOglycine is added (6.0 g, 11.9 mmol) with ethanol (500 ml), then potassium hydroxide (1.34 g, 23.8 mmol) is added.

The mixture obtained is stirred overnight at room temperature. Concentrated hydrochloric acid is added dropwise, with stirring, to pH 3. Water (about 500 ml) is added, and the reaction mixture is filtered. The filtrate is evaporated, which gives a colorless solid. Ether is added to the residue, and the solid is filtered, then washed with ether, which gives the product in the form of a colorless solid,
F = 205-210.

Composition, calculated for
C14H19ClN4O6S2.HCl.H2O: C, 34.08; H, 4.50; N, 11.36.

 Found: C, 34.36; H, 4.58; N, 11.69.

D. Ethyl ester of 1> N- [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl [-N- (2,2,2-trichloro-ethoxycarbonyl) -L-alanyl] -N- [ 4-spiro (6-chloro-3,4-dihydro7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-l-yll-qlycine:
To a solution of N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -N- (2,2,2-trichloroethoxycarbonyl) -L-alanine (2.76 g, 6.07 mmol) in dry methylene chloride (15 ml) at room temperature, under a nitrogen atmosphere, oxalyl chloride (1.6 ml) is added dropwise, then dimethylformamide (12 p1). The reaction mixture is stirred for three hours at room temperature. The methylene chloride is evaporated and toluene is added to the residue. The toluene is removed in vacuo (T less than 500), then another part of the toluene is removed in vacuo (T less than 500) and the residue is placed under a high vacuum (oil pump) for 30 minutes. The residue is dissolved in dry methylene chloride (7 ml), it is placed in a nitrogen atmosphere and this solution is cooled to -10 ° C., a solution is then added dropwise over 10 minutes. N-L4-spiro ethyl ester hydrochloride (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl3glycine (3 , 17 g, 6.22 mmol) and triethylamine (3.80 ml) in dry methylene chloride (28 ml). The mixture is slowly warmed to room temperature and then stirred overnight.

The methylene chloride is evaporated, then the residue is dissolved in ethyl acetate. The organic solution is washed twice with 0.1 N HCl, twice with water, once with brine, dried over magnesium sulfate, filtered and evaporated, which gives the crude product in the form of a light yellow oil. The crude product is purified by HPLC using the ethyl acetate / n-hexane / ethanol solvent system (60: 30: 5) as eluent.

In this way, the title compound is separated into two diastereoisomers having Rf (silica gel) of 0.369 and 0.536 in the above solvent system.

The compound with an Rf of 0.369 has a melting point of 165-170, and the compound with an Rf of 0.536 has a melting point of 158-160. The main product is the one with an Rf of 0.369 (about 9: 1).

Composition: calculated for C34H43C14N5OllSl2
C, 45.19; H, 4.80; N, 7.75.

 Found: C, 45.91, H, 4.90; N, 7.48.

 Rf = 0.369; F = 165 - 1700.

Composition: calculated for C34H43Cl4N5O11S2.C4H100:
C, 46.67; H, 5.44.

 Found: C, 46.69; H, 4.92.

 F = 158 - 1600.

E. N- (NE (îS) -i-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N- [4-spiro (6-chloro3,4-dihydro-7-sulfamoyl-1) ethyl ester , 2,4-benzothiadiazine-1,1dioxide) cyclohex-1-yl] glycine:
N- (Nr (1S) - 1-ethoxycarbonyl-3-phenylpropyl] -N- (2,2,2-trichloroethoxycarbonyl) -L-alanyl] -N- [4-spiro (ethyl ester) is dissolved. 6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl] -glycine (0.62 g, 0.686 mmol) in acid glacial acetic acid (6 ml), then zinc powder (1.8 g) is added in successive portions and the mixture obtained is placed under nitrogen and the reaction mixture is stirred at room temperature for 1.5 hours.

The zinc is separated by filtration and washed with a small amount of glacial acetic acid. It is evaporated in vacuo (T less than. 450) Toluene is added to the residue, then it is evaporated in vacuo (T less than 450). The residue is placed under a vacuum
pushed (oil pump) for about an hour, then ether is added to the residue which gives the desired product, after scraping, in the form of a colorless solid which is filtered and washed with ether, F = 1800, it has the following structure

Example 2
N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N- [4-spiro (6-chloro-3,4-dihydro-7 sulfamoyl-1) hydrochloride , 2,4-benzothiadiazine-1,1-dioxide) -cyclohex- 1-yl] glycine
N [N - ((1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N- [4-spiro (6-chloro 3,4-dihydro-7-) ethyl ester sulfamoyl-1 e 2,4-benzothiadiaz-îneW dioxide) cyclohex-1-yl] glycine (0.50 g, 0.688 mmol) is added to 50 ml of ethanol and placed under nitrogen then 1N NaOH (40 ml) is added and the reaction mixture is stirred at room temperature overnight. Most of the ethanol is evaporated in vacuo (T less than 450). Water (about 100 ml) is added to the residue and then added. drop by drop of concentrated hydrochloric acid, with stirring, until a pH of approximately 3 is obtained. The product is extracted several times with ethyl acetate, dried over magnesium sulfate, filter and evaporate to give a solid, add ethanol to the residue and filter the solid, then wash with ethanol, F = 1600.

Composition: calculated for C27H34ClN5OgS2 .2HC1.CH3CH2OR: C, 42.08; H, 5.12
N, 8.46.

 Found: C, 42.09; H, 4.64; N, 8.20.

Example 3
A. Ethyl ester of N # -carbobenzoxylysine:
To N # -carbobenzoxylysine (69.7 g), ethanol (1000 ml) was added which was saturated with anhydrous hydrochloric acid. The solution obtained is stirred at room temperature for three days. The ethanol is evaporated in vacuo and the residue is taken up in chloroform (500-600 ml). The chloroform is washed twice with saturated aqueous sodium bicarbonate, filtered and evaporated to give the desired product as a colorless oil (69.9 g).

B. Ethyl ester of N α - [4- (2,2-dimethyltrimethylene ketal) cyclohex-1-yll-NE-carbo-benzoxy-
L-lysine
Ng-carbobenzoxylysine ethyl ester (22 g, 71.3 mmol) and 1,4-cyclohexanedione riono-2,2-dimethyltrimethylene ketal (10.0 g, 50.4 mmol) are dissolved in absolute alcohol (350 ml) in a round bottom flask fitted with a desiccant tube (CaSO4). The reaction mixture is cooled to 50C by means of an ice-water bath, then sodium cyanoborohydride (1.99 g) is added in successive portions over a period of 30 minutes. The ice-water bath is removed, and the reaction mixture is stirred overnight at room temperature. The ethanol is evaporated and water is added to the residue. The product is extracted several times in chloroform, washed once with water, twice with 10% aqueous sodium bicarbonate, again with water, it is dried over magnesium sulphate, it is filtered and it is evaporated, which gives the crude product. The crude product is purified by HPLC on silica gel using the chloroform-acetone solvent system (9: 1). The desired product is thus obtained in the form of a colorless oil.

Composition: calculated for C27H42N2O6.1 1 / 2H2O
C, 62.64; H, 8.76; N, 4.41.

 Found: C, 62.56; H, 8.48; N, 4.20.

C. N & alpha ethyl ester - [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl - 1,2,4-b-enzothiadiazinew dioxide) cyclohex-1-yl] -Ne-carbobenzoxylysine
Dissolving ethyl ester of N- (4- (2,2-dimethyltrimethylene ketal) cyclohex-1-yl] -Nc-carbo-benzoxy-L-lysine (4.0 g, 8.15 mmol) and 1-amino-3chloro-4,6-benzene disulfonamide (232 g, 8.15 mmol) in ethanol (125 ml) which has been previously saturated with anhydrous hydrochloric acid. The mixture is stirred obtained for three days at room temperature. Ether (about 250 ml) is added to the reaction mixture, the solid is filtered and washed with a small amount of ether. In this way, the desired product is obtained. , the hydrochloride, in the form of a colorless solid (4.53 g), F = 225-2270.

Composition: calculated for C28H38ClN5O8S2.1 1 / 2H2O
C, 48.09; H, 5.91; N, 10.02.

 (free base) Found: C, 48.37; H, 5.92; N, 9.40.

D. N & alpha ethyl ester - [NI (1S) -1-ethoxycarbonyl-3-phenylpropyl] -N- (2,2,2-trichloro - ethoxycarbonyl) -L-ålanyl] -Na- r 4-spirot6 - chloro-3-, 6-dihydro- 7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) -cyclo hex-1-yl] -N @ -carbobenzoxylysine:
To a solution of N - [(1S) -1-ethoxycarbonyl-3phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanine (2.0 g, 4.40 mmol) in dry methylene chloride (15 ml) at room temperature, under a nitrogen atmosphere, oxalyl chloride (1.5 ml) is added dropwise then dimethylformamide (12 v1). The solution obtained is stirred for three hours at room temperature. The methylene chloride is evaporated and toluene is added to the residue. The toluene is removed in vacuo (T less than 50), then another portion of toluene is added to the residue. The toluene is again evaporated in vacuo (T less than 500), and the residue is placed in a vacuum. push (oil pump) for one hour. The residue is dissolved in dry methylene chloride (10 ml), placed under nitrogen and cooled to 50C. To this solution is then added dropwise, over a period of 10 minutes, a solution of hydrochloride of the ethyl ester of
N α - [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4benzOthiadiazine-l, l-dioxide) cyclohex-l-yl] -N-carbo- benzoxylysine (2,2 g, 3.10 mmol) and triethylamine (2.0 g) in dry methylene chloride (20 ml).

The mixture is slowly heated to room temperature and then stirred overnight. The methylene chloride is evaporated, then the residue is dissolved in ethyl acetate. We wash it. organic solution twice with 0.1N HCl, twice with 10% aqueous sodium bicarbonate, twice with water, dried over magnesium sulfate, filtered and evaporated to give the product in the form of an orange-colored glass. Ether is added to the residue, which causes the glass described above to solidify in the form of an amorphous solid. The solid is filtered and washed with ether to give the desired product as a white solid (2.3 g), F - 1530.

Composition: calculated for C46H58Cl4N6O13S2.2 1 / 2H2O:
C, 47.87; H, 5.50; N, 7.28.

 Found: C, 47.86; , 5.13; 7.11.

E. Na- [NL (lS) -1-ethoxycarbonyl-3-phenylpropyl] -N- (2,2,2-trichloroethoxycarbonyl) -L-alanyl] -N & alpha ethyl ester - [4 - (2,2-dimethyltrimethylene ketal) cyclohex-1-yl] -N # -carbobenzoxy-L-lysine:
To a solution of N - [(1S) -1-ethoxycarbonyl-3phenylpropyl] -N- (2,2,2-trichlorethoxycarbonyl) -L-alanine (2.76 g, 6.07 mmol) in dry methylene chloride (15 ml) at room temperature, under a nitrogen atmosphere, oxalyl chloride (1.6 ml) is added dropwise, then dimethylformamide (12 μl). The solution obtained is stirred for three hours at room temperature. Methylene chloride is evaporated (T less than 45), and toluene is added to the residue.

 The toluene is removed in vacuo (T less than 450), then another portion of toluene is added to the residue.

The toluene is again evaporated in vacuo (T less than 450), and the residue is placed under a high vacuum (oil pump) for one hour. The residue is dissolved in dry methylene chloride (7 ml), it is placed in a nitrogen atmosphere, and it is cooled to -100. This solution is then added dropwise over 10 minutes. , ethyl ester of N α - [4- (2,2-dimethyltrimethylene ketal) cyclohex-1-yl] -N # -carbobenzoxy-L-lysine (3.09 g, 6.29 mmol) and triethylamine (1.5 ml) in methylene chloride (20 ml). The cooling bath is removed and the reaction mixture is stirred overnight at room temperature. Water is added to the reaction mixture, then the product is extracted three times in methylene chloride, washed twice with bicarbonate of saturated aqueous sodium, twice with water, dried over magnesium sulphate, filtered and evaporated, which gives the crude product in the form of a reddish colored oil. The crude product is purified by chromatography on silica gel using the methylene chloride / acetone solvent system (95: 5) as eluent. The product is reacted with 1-amino-3-chloro-4,6-benzene disulfamide as in stage C of this example, this constituting another route for obtaining the product in stage D.

F. N & alpha ethyl ester hydrochloride - [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl]
N α - [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4benzothiadiazine-1,1-dioxide) cyclohex-1-yl] -N # -carbobenzoxylysine:
Na-LN ethyl ester - [(1S) -i-ethoxycarbonyl-3-phenylpropyl] -N- (2,2,2-trichlorethylcarbonyl) -
L-alanyla-Na- [4-spiro (6-chloro-3t4-dihydro-7-sulfamoyl- 1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-l-yl] -N # - carbobenzoxylysine (1 , 93 g, 1.74 mmol) is dissolved in a mixture of CH2C12 / HOAC (20 ml / 5 ml, respectively) then zinc powder (6.0 g) is added in successive portions, and the system is placed under a nitrogen atmosphere. The reaction mixture is stirred at room temperature for 2.5 hours, the zinc is filtered and washed with a small amount of glacial acetic acid and methylene chloride.

Anhydrous hydrochloric acid is bubbled through the filtrate for about 5 minutes. The filtrate is concentrated in vacuo (T below 450).

Ethyl acetate and water are added to the residue, then concentrated ammonium hydroxide is added dropwise until a pH of 8-9 is obtained. The free base is extracted several times in ethyl acetate. The combined organic extract is washed once with water, dried with magnesium sulfate, filtered and evaporated, which gives the product in the form of a light yellow oil (0.71 g ).

G. N & alpha chiorhydrate; - [N - [(1S) -carboxy-3-phenylpropyl] -L-alanyl] -N α - [4-spiro (6-chloro-3,4-dihydro- 7sulfamoyl-1,2,4-benzothiadiazine-- -dioxy-de? -CZclohex- l-yl3-NE-cabobenzoxylysine:
N α - [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] -N α - [4-Spiro (6-chloro-3,4-dihydro-7-sulfamoyl) -1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl] -N # -carbobenzoxylysine (0.60 g, 0.644 mmol) in ethanol (20 ml), then 1N NaOH is added (10 ml).

The mixture obtained is stirred overnight at room temperature. Most of the ethanol is evaporated under vacuum (T less than 45). Water is added to the residue, then dropwise concentrated hydrochloric acid until a pH of approximately 2 is obtained. The product is extracted several times in ethyl acetate and dried. on magnesium sulphate, it is filtered and it is evaporated, which gives the desired product in the form of a colorless solid.

H. N & alpha dihydrobromide - [NI (1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N α - [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl- 1,2,4-benzothiadiazine-1,1 dioxide) -cyclohex-l-yl Ulysine:
Na-CN hydrochloride [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N α -4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-) is suspended 1,2,4-benzothiadi azine-l, l-dioxide) -cyclohex-l-yl] -NE -carbobenzoxylysine (0.2 g, 0.228 mmol) in dry methylene chloride (40 ml), then add drop 25 drops of
HBr in acetic acid (40% solution). The reaction mixture is capped slightly and stirred at room temperature for two hours. The reaction mixture is concentrated on a rotary evaporator (T less than 450), then placed under a high vacuum (oil pump) for one night. Ether is added to the residue, the solid which forms is filtered and washed with a small amount of ether. In this way, the desired dihydrobromide (0.146 g) is obtained in the form of a white-slightly tinted solid,
F = 130-132.

Composition: calculated for C31H43ClN6O9S2.3HBr
C, 37.76; H, 4.70.

 Found: C, 38.11. H, 4.88.

The following compounds are prepared using the procedures described in Examples 1 to 3
Example 4 N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -N- [3- spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1, 2,4-benzo thiadiazine-l, l-dioxide) -2-methylcyclopent-1-ylaglycine (see formula (1):

X1 = -CH (CH3) -; X2 = - (CH2) -2.
Example 5
N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N- [5spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine -1,1-dioxide) cyclooct-1-yl] -L-alanine (see formula (1): Z = -CH; X1 = X2 = - (CH2) 3-).

Example 6
N α - [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -N α - [3spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2, 4-benzothiadiazine-1,1-dioxide) -thian-5-yl] -L-lysine (see formula (1): Z = -CH; X1 = - CH2-; X2 = -CH2SCH2-).

Example 7
N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N- [3 spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4- benzothiadiazine-1,1-dioxide) -piperidin-5-yl] glycine (see formula (1): Z = -CH; X = -CH2-, X2 = -CH2NHCH2-).

Example 8
N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N- [4spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine -1, 1-dioxide) -piperidin-1-yl] glycine (see formula (1): Z = - #; X1 = X2 = - (CH2) 2 -).

Example 9
N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N- [5spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine -1,1-dioxide) -3-hydroxy-cyclohex-1-yl] glycine (see formula (1): Z = - #; X1 = -CH2-; X2 = -CH2CHOHCH2-)
Example 10 N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -N- [7- spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1, 2,4-benzothiadiazine-1,1-dioxide) -5,6,7,8-tetrahydroisoquino lein-5-yl] -L-alanine (see formula (1):
Z = -CH

X2 = -CH2-).

Example II
N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -N- [3spiro (6-chloro-3,4-dihydro-7-sulfamoyl-lt2,4-benzo- thiadiazine-1,1-dioxide) -indan-1-yl] glycine (See formula (1): Z = -CH; X1 = -C = C-; X2 = -CH2-).

 Example 12 (S) -N- [3-acetylthio; 2 "methylpropanoyl] -N-d-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl] glycine.

 Example 13 (S) -N- [3-mercapto-2-methylpropanoyl] -N- [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1 -dioxide) -indan-1-yl] -L-alanine.

Example 14
N- [3- (2,2,2, -trimethylacetylthio) -2-methylpropanoyl]
[3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzo thiadiazine-l, l-dioxide) -cyclopent-l-yl3glycine.

Example 15
N- [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl]
N- [4- (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothia
diazine-1,1-dioxide) -cyclohex-1-yl] glycine.

Example 16
N α - [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl
N α - [4- (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothia-
diazine-1,1-dioxide) -cyclohex-1-yl] lysine.

Example 17
N- [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] N- [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-
benzothiadiazine-1,1-dioxide) -indan-2-yl] glycine.

Claims (9)

1. Compound corresponding to formula (1)

 and its acid addition salts, pharmaceutically acceptable alkali metal and alkaline earth metal salts, wherein  Q is Y1-C (O) -C * H (R1) -NH-, -NH2, R1-C (O) -S-C * H (RA)) 0-1-, or US- (C * H (R1)) 0-1-) Y1 and

 independently have - OH, -OR, or-NR1R2 Z is  / or -N  one of the indices x and y is 1 and the other is O  R is independently hydrogen, alkyl C1 to C81 an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms, and the alkyl part has I to 6 carbon atoms, a cycloalkyl having 3 to 10 atoms carbon, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or an amino-substituted alkyl group having 1 to 6 carbon atoms,  R1 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a fused cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or a substituted amino alkyl group having 1 to 6 carbon atoms;  R2 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having ~ up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a condensed cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or an alkyl group having 1 to 6 carbon atoms, which is substituted by -NH , -NH-C (NH2) = NH2, or

 X1 is- (CH2) a - @ - (CH2) bS (CH2) c-.  A, B and E are independently hydrogen, halogen, -OH, -OR, -CF3, -NR1R2, -C (O) Y1, -SO2R, -SO2NR1R2, provided that at least two of the radicals A, B and E are not hydrogen;  R6 is independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an aryl-alkyl in which the aryl part has up to 10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a fused cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group or an amino-substituted alkyl group having 1 to 6 carbon atoms;  R4 and R5 are independently hydrogen, an alkyl having 1 to 8 carbon atoms, an aryl having up to 12 carbon atoms, an alkyl-aryl in which the aryl portion has up to -10 carbon atoms and the alkyl part has 1 to 6 carbon atoms, a cycloalkyl having 3 to 10 carbon atoms, a fused cycloalkylaryl having 8 to 12 carbon atoms, a heterocyclic group, or an amino substituted alkyl group having 1 to 6 carbon atoms;  R3 is -OH, phenyl, or an alkyl or alkoxy group having up to 6 carbon atoms;

- (CH2) bN (R) (CH2) e-, - (CH2) @C (O) (CH2) c-, - (CH2) bCH (R3) (CH2) c-,  provided that a, b, c, d, e, f, g and h are each zero or a positive integer up to 6, and are chosen so that the ring formed by X1 'X2 and the two atoms to which they are fies, contain 5 to 8 atoms; in which the condensed alkyl, cycloalkyl, aryl and aryl-cycloalkyl groups can carry substituents chosen from the group consisting of an alkyl having 1 to 6 carbon atoms, an alkoxy having 1 to 6 carbon atoms, -CF3, - OH, -SH, halogen, -NO2 'and -COOR.  (CH2) eCH (R3) (CH2) f-;  (CH2) bN (R) (CH2) e-, - (CH2) e C (O) (CH2) f-, or  X2 is - (CH2) d-, - (CH2) e S (CH2) f-,  2. A compound or salt according to claim 1, wherein each asymmetric spiro carbon atom is in the (S) or (R) configuration and the other asymmetric carbon atoms are in the (S) configuration.  3. A compound or salt according to claim 1 wherein E! R4 and R5 are hydrogen and Z is-C * H-,  4. A compound or salt according to claim 3, in which X1 is - (CH2) a- and X2 is - (CH2) of  5. Compound and salts thereof according to claim 1 which is the ethyl ester of N- [N- (1S) -1-ethoxycarbonyl-3-phenylpropyl] -L-alanyl] N- [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4benzothiadiazine-1,1-dioxide) cyclohex-1-yl] glycine.  6.- Compound and salts according to claim 1, which is the hydrochloride of N- [N - [(1S) -1-carboxy3-phenylpropyl] -L-alanyl] -N- [4-spiro (6-chloro- 3,4 dihydro-78ulfamoyl-1,2,4-benzothiadiazine-l, l-dioxide) - cyclohex-1-yl] glycine.  7.- Compound and its salts according to claim 1, which is the N & alpha dihydrobromide; - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] -N α - [4-spiro (6- chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) cyclohex-1-yl j lysine.  8. Pharmaceutical preparation comprising an effective amount as a hypertensive of a compound or salt according to claim 1, associated with a pharmaceutically acceptable carrier.  N [[N - [(1S) -1-carboxy-3phenylpropyl] -L-alanyl] -N [5-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine- 1,1-dioxide) -cyclooct-1-yl] -L-alanine.  9. Compound according to any one of claims 1 to 4 which is one of the following compounds: s N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -N - [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) -2-methylcyclopent-1-yl] glycine N- α - [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4- benzothiadiazine-1,1-dioxide) -thian-5-yl] -L-lysine.  N α - [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] N-t3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4 benzothiadiazine-1,1-dioxide) -piperidin-5-yll glycine.  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl]  N- [N- t (1S) -1-carboxy-3-phenylpropyl - N- [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1t2,4- benzothiadiazine-1,1-dioxide ) -piperidin-1-yl] glycine.  N- [N - [(1S) -1-carboxy-3-phenylpropyl] -L-alanyl] N-r5-spiro (6-chloro ~ 3,4-dihydro-7-sulfamoyl-1,2,4- benzothiadiazine -1,1-dioxide) -3-hydroxy-cyclohex-1-yl] glycine. N- [7-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4- benzothiadiazine-1,1-dioxide) -5,6,7,8-tetrahydroisoquinoline-5-yl] -L-alanine.  N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] N- [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4 benzothiadiazine-l, l-dioxide) -indan-l-ylAglycine.  N- [N α - [(1S) -1-carboxy-3-phenylpropyl] -L-lysyl] -  (S) -N- [3-acetylthio; -2-methylpropanoyl] -N- [4-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzOthiadiazine-1, l-dioxide) -cyclohex - ylglycine.  (S) -N- [3-mercapto-2-methylpropanoyl] -N- [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1 -dioxide) -indan-1-yl] -L-alanine.  3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide) -cyclopent-1-yl-glycine.  N- [3- (2,2,2-trimethylacethylthio) -2-methylpropanoyl  N- [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -Lalanyl] -N- [4- (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4 benzOthiadiazine-1 , l-dioxide) cyclohex-l-yl] glycine.  Na- [N - [(ls) -l-ethoxycarbonyl-3-phenylpropyl] -L- alanyl] -N α - [4- (6-chloro-3,4-dihydro-7-sulfamoyl-1,2,4benzOthiadiazine -l, l-dioxide) cyclohex-l-yl] lysine.  N- [N - [(1S) -1-ethoxycarbonyl-3-phenylpropyl] -Lalanyl] -N- [3-spiro (6-chloro-3,4-dihydro-7-sulfamoyl 1,2,4-benzothiadiazine- l, l-dioxide) indan